This proposal establishes a new collaboration spanning molecular, cellular, tissue, and whole-organ levels of modeling to develop a multi-scale model of cardiac metabolism. We have assembled a team of researchers at Medical College Wisconsin and University of Auckland with expertise in computational modeling and quantita-tive analysis of cardiac physiology necessary to develop a self-consistent integrated description of the relevant biophysical processes. We have assembled a team of researchers with expertise in computational modeling and quantitative analysis of cardiac physiology necessary to develop a selfconsistent integrated description of the relevant biophysical processes at molecular, cellular, tissue, and whole-organ levels of resolution. Our specific aims are: (1.) Cellular and subcellular modeling: we will develop a cellular model integrating myocardial energy metabolism, the cardiac action potential and the cellular contractile apparatus, to predict the cellular response to ischemia, hypoxia, hyperglycemia, and/or dyslipidemia; (2.) Integration of microvascular transport and coronary blood flow: whole-organ models of the coronary vasculature will be linked with models and associated numerical methods for simulating transport and exchange of solutes in the coronary capillary, network; and (3.) Model-ing the beating heart in health and disease: metabolic and transport processes will be incorporated into the exist-ing Auckland heart/model, which currently treats the electrophysiology and mechanics of cardiac contraction. The multi-scale integrative framework developed in this proposal will provide new insights and enable predic-tion of the mechanisms of metabolic function and dysfunction in the heart. Our long-term goal (and indeed a major long-term goal of computation biology in general) is to develop the computational power to simulate the metabolic and regulatory mechanisms acting in disease and to quantify the impact of therapeutic agents on these mechanisms. By developing a platform to simulate wholeheart function under a variety of pathophysiological settings, including hypertrophy, hypertension, hyperglycemia, and combi-nations of these factors, the developed model will serve as a prototype for the future applications in the com-puter-aided design and optimization of therapeutics.